Establishment and characterization of a childhood pre-B acute lymphoblastic leukemia cell line, PER-278, with chromosome translocations t(1;19) and t(1;9)

Cell line PER-278 was established from a bone marrow sample of a 10-year-old boy diagnosed with pre-B acute lymphoblastic leukemia (ALL). PER-278 cells show the pre-B phenotype, express cytoplasmic Ig, and exhibit two translocations: t(1;19)(q23;p13) and t(1;9)(q23;p13). Assessment of the immunoglobulin rearrangements confirmed the clonal origin of cell line PER-278, and comparison with the patients's leukemic cells showed an identical pattern: loci involved at the breakpoint on chromosome 1 code for the oncogene SKI and for the Fc receptor II and on chromosome 19 for the insulin receptor. The t(1;19) may contribute to the malignant transformation in leukemic cells of pre-B phenotype.     

A complex t(3;8;17) involving breakpoint 8p11 in a case of M5 acute nonlymphocytic leukemia with erythrophagocytosis

The t(8;16)(p11;p13) is a recently described new chromosome rearrangement of acute nonlymphocytic leukemia (ANLL). It appears to be specifically associated with acute monoblastic (AML-M5) or unusual myelomonocytic leukemia with prominent erythrophagocytosis in the leukemic cells. A complex t(3;8;17)(q27;p11;q12) is reported in a case of acute monoblastic leukemia with erythrophagocytosis. Sixteen cases of this t(8;16) and two other variant translocations are reviewed. The pathogenetic mechanism of the variant translocations is discussed, suggesting that the der(8) is a consistent recombinant.     

Atypical (7;19) translocation in acute myelomonocytic leukemia.

Chromosome studies were carried out after a 24-hour harvest of unstimulated bone marrow aspirate cell cultures from a 75-year-old male with a clinical diagnosis of acute myelomonocytic leukemia (FAB M4). Analysis of nine cells after trypsin-Giemsa banding (GTG) revealed two cell lines with a mosaic chromosome pattern, 46,XY/46,XY,t(7;19)(q22;p13.3). A review of the recent literature reveals one case of childhood ALL with a 46,XY/46,XY,t(7;19)(q11;q13) chromosome pattern [1] and a 46,XY,t(3q;11q),t(7q;19p),t(15;17)(q26;q22) in one patient with ANLL (FAB M3) [2]. The t(7;19)(q22;p13.3) seen in our case has not been reported as the sole specific clonal chromosome rearrangement in myeloid neoplasia. Interestingly, the plasminogen activator inhibitor type I, multi-drug resistance, and erythropoietin genes are located at band 7q22 and the insulin receptor gene is located at band 19p13.3. Both sites contain fragile site loci. The possible role of these fragile sites, genes, or other genes in the rearrangement can only be surmised.     

Isodicentric 20q- in two cases of B-cell acute lymphocytic leukemia with the respective t(9;20)(p11;q11.2) and t(9;22)(q34;q11.2)

The cytogenetic anomaly der(20)del(20)(q11.2q13.3)idic(20)(p11), or idic(20q-) in short form, has been reported in 13 cases of myelodysplastic syndrome, one case of chronic myelomonocytic leukemia, and one case of acute myeloid leukemia since 2004. To our knowledge, it has not previously been described in lymphoid diseases. Here we report the cases of two patients with B-cell acute lymphocytic leukemia (ALL) having a novel idic(20q-). One was a 34-year-old man with B-cell ALL whose leukemic cells at presentation had a karyotype of 45,XY,dic(9;20)(p11;q11.2); at relapse, a small marker chromosome was found coexisting with the dic(9;20). The other was a 39-year-old woman with Ph-positive B-cell-ALL whose leukemic cells contained both t(9;22)(q34;q11.2) and a small marker chromosome. A series of FISH analyses using the appropriate probes revealed the small marker chromosome in both patients to be an idic(20q-), confirming the dic(9;20)(p11;q11.2) in one case and revealing a BCR/ABL fusion gene in the other. One patient achieved complete remission but relapsed; the other did not achieve complete remission. Both patients died with a short survival time, despite receiving intensive chemotherapy. These two cases show that idic(20q-) can appear not only in myeloid diseases but also in lymphoid diseases.     

Precursor T-lymphoblastic leukemia with a novel t(1;22)(p34;q13)

A 37-year-old woman that presented with cervical lymphadenopathy and leukocytosis was found to have precursor T-lymphoblastic leukemia (T-ALL). Cytogenetic study of the leukemic cells showed a 46,XX, t(1;22)(p34;q13) karyotype. The t(1;22)(p34;q13) is a novel chromosomal abnormality in human malignancies and is probably a variant form of the t(1;14)(p34;q11) found in precursor T-ALL.     

Unbalanced translocation der(11)t(11;12)(q23;q13): a new recurrent cytogenetic aberration in myelodysplastic syndrome with a complex karyotype

Cytogenetic abnormalities are observed in approximately one half of cases of myelodysplastic syndrome (MDS). Partial or complete chromosome losses and chromosome gains are frequently found, but there is a relatively high incidence of unbalanced translocations in MDS. We describe here two cases of MDS with an unbalanced translocation, der(11)t(11;12)(q23;q13). Both patients were 69 years of age and diagnosed with refractory anemia with excess of blasts in transformation (RAEB-t) according to the high percentage of blasts in the peripheral blood. Cytoplasmic hypogranulation of neutrophils was evident as a dysplastic change. The blasts were positive for CD4 and CD41a as well as CD13, CD33, CD34 and HLA-DR in both cases. Chromosome analysis showed complex karyotypes including a der(11)t(1;11)(q11;p15)t(11;12)(q23;q13) in case 1 and der(11)t(11;12)(q23;q13) in case 2 plus several marker chromosomes. Spectral karyotyping confirmed the der(11)t(11; 12)(q23;q13) and clarified the origin of marker chromosomes, resulting in del(5q) and del(7q). Fluorescence in situ hybridization (FISH) analyses with a probe for the MLL gene demonstrated that the breakpoints at 11q23 were telomeric to the MLL gene in both cases. FISH also showed that the breakpoint at 11p15 of the case 1 was telomeric to the NUP98 gene. Considering another reported case, our results indicate that the der(11)t(11;12)(q23;q13) is a recurrent cytogenetic abnormality and may be involved in the pathogenesis of advanced-stage MDS.     

Translocation t(11;14)(q13;q32) in chronic lymphoid disorders.

The translocation t(11;14)(q13;q32) has been described in a spectrum of B-lymphoproliferative diseases and involves a putative oncogene, BCL1, which maps to chromosome band 11q13. Recent evidence indicates that this abnormality may delineate particular subtypes of lymphoma, such as intermediate lymphocytic and centrocytic lymphomas. Thus the possible significance of the t(11;14) within B-cell disorders should be reexamined in the light of a more objective approach to classifying these diseases by morphology, histology, and immunophenotype. We describe 16 patients with t(11;14)(q13;q32) from a series of 90 patients with chronic lymphoid disorders in whom clonal chromosome abnormalities were detected. All the cases were leukemic: prolymphocytic (B-PLL; 4/15 cases), chronic lymphocytic leukemia (CLL) with increase in prolymphocytes (2/9 cases), or non-Hodgkin lymphoma in leukemic phase, intermediate (3/4 cases), lymphoplasmacytic (2/2 cases), splenic lymphoma with villous lymphocytes (4/18 cases), and follicular (1 case). None of the CLL (25) or hairy cell leukemia cases (15) had t(11;14). Our findings showed that t(11;14) occurred in leukemias of mature B cells with lymphoplasmacytic features as judged by morphology and immunophenotype.     

Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop

Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities.     

Precursor B lymphoblastic leukemia with surface light chain immunoglobulin restriction: a report of 15 patients

We describe 15 patients (9 children) with precursor B-cell (pB) acute lymphoblastic leukemia (ALL) with surface immunoglobulin (sIg) light chain restriction revealed by flow cytometric immunophenotyping (FCI). The same sIg+ immunophenotype was present at diagnosis and in 3 relapses in 1 patient. In 15 patients, blasts were CD19+ CD10+ (bright coexpression) in 14, CD34+ in 12, surface kappa+ in 12, surface lambda+ in 3; in 8 of 8, terminal deoxyribonucleotidyl transferase (TdT)+; and in 4, surface IgD+ in 2 and surface IgM+ in 1. The 3 CD34- cases included 1 TdT+ case, 1 with t(1;19)(q23;p13), and 1 infant with 70% marrow blasts. One adult had CD10- CD19+ CD20- CD22+ CD34+ TdT+ sIg+ blasts with t(2;11)(p21;q23). Blasts were L1 or L2 in all cases (French-American-British classification). Karyotypic analysis in 12 of 12 analyzable cases was negative for 8q24 (myc) translocation. Karyotypic abnormalities, confirmed by fluorescence in situ hybridization in 6 cases, included hyperdiploidy, t(1;19)(q23;p13), t(12;21)(p13;q22), t(9;22)(q34;q11), t(2;11)(p21;q23), and trisomy 12. The sIg light chain restriction in pB ALL might be present in neoplasms arising from the early, intermediate, and late stages of precursor B-cell maturation; sIg light chain restriction revealed by FCI does not necessarily indicate a mature B-cell phenotype, further emphasizing the importance of a multidisciplinary approach to diagnosing B-lymphoid neoplasms.     

Transposition of the oncogene ets-1 in t(11;19) translocation in acute leukemia

The specific chromosomal rearrangement t(11;19)(q23;p13) has been identified as a nonrandom chromosomal rearrangement in acute leukemia. The breakpoint, 11q23, coincides with the ets-1 oncogene locus. However, only very few studies have been done to verify the genomic alteration and transposition of ets-1 in the t(11;19) chromosomal rearrangement. In the present study, we identified the t(11;19)(q23;p13) translocation in two acute leukemic cases. One of the cases, biphenotypic leukemia, has been followed thoroughly. An abnormal karyotype was identified in the patient's blood and marrow samples at diagnosis and at relapse, while only normal karyotypes were identified at remission.

In situ hybridization of chromosomal preparations with the ets-1 probe pHE5.4 resulted in silver grains nonrandomly localized to 19p13 in the metaphase spreads prepared from the blood sample taken at relapse, while no detectable grains were found on chromosome 19p13 in a sample taken at remission. To determine if genomic alterations of ets-1 are associated with this translocation, Southern blot hybridizations with the pHE5.4 probe were performed on deoxyribonucleic acid (DNA) isolated from blood or marrow samples of the patient at remission and relapse as well as on DNA from a disease-free normal control. Any DNA digested with AvalI, SstI, XbaI, and Bam HI, followed by hybridization with pHE5.4, demonstrated no genomic alterations or amplification of the ets-1 oncogene. Our study indicates that the ets-1 oncogene is transposed in the t(11;19) translocation without detectable alteration at the DNA level. The absence of ets-1 amplification in t(11;19) and its presence in the t(4;11) and t(9;11) translocations demonstrated by others suggests the possible existence of different molecular mechanisms involving the ets-1 oncogene in the pathogenesis of these leukemias.     

11q23异常恶性血液病的临床和细胞遗传学研究

目的 评估１１ｑ２３异常与恶性血液病的临床,血液学和预后的相互联系。方法 采用骨髓直接法和（或）培养法制备色体标本,用Ｒ显带技术,对６０００例恶性血液病进行核型分析。结果 ６０００例恶性血液病中发现２８例有１１ｑ２３异常,发生率为０．４７％。异常类型有７种：ｔ（４;１１）（ｑ２１;ｑ２３）１０例;ｔ（１１;１９）（ｑ２３;ｐ１３）５例;ｔ（９;１１）（ｐ１２;ｑ２３）２例;ｔ（１０;１１）（ｐ１５     

Variant translocations (9;11): identification of the critical genetic rearrangement

The t(9;11)(p22;q23) is a recurring abnormality in acute nonlymphocytic leukemia. The analysis of complex 9;11 translocations will aid in the identification of the conserved chromosomal junction or the critical genetic alteration created by the rearrangement; however, variant translocations involving chromosomes #9 and #11 have not been reported. We have identified such variants in two patients who had acute myelomonocytic leukemia and acute monocytic leukemia, characterized by a t(9;11;18)(p22;q23;q12) and a t(9;11;13)(p22;q23;q34), respectively. The conserved junction resulting from these rearrangements is created by the translocation of chromosomal material from 9p to 11q.     

Comprehensive cytogenetic analysis including multicolor spectral karyotyping and interphase fluorescence in situ hybridization in lymphoma diagnosis. a summary of 154 cases

Cytogenetic analysis including multicolor spectral karyotyping (SKY) and interphase fluorescence in situ hybridization (FISH) was performed on 154 consecutive cases with suspected lymphoma. The cytogenetic results were reviewed in correlation with the final pathologic diagnosis. A diagnosis of lymphoma was established in 94 cases, with 16 Hodgkin lymphomas and 78 non-Hodgkin lymphomas (NHL). Cytogenetic results were obtained in 63 NHLs (81%); 61 of those showed abnormal karyotypes (97%). The t(14;18) or IGH-BCL2 fusion was detected in 83% (20/24) of follicular lymphomas and in 57% (12/21) of diffuse large B-cell lymphomas (DLBCL). The application of interphase FISH and SKY has contributed to a high detection rate of t(14;18) in DLBCLs. This study showed that genes at 1q25, 3p21, 3q21, 5q31, 6p23, 7q22, 8q11 approximately q12, 9q34, 11q23, 12q13, and 19q13.1 may have been involved as the less common changes in follicular lymphoma and DLBCL. Comparison of the recurrent secondary aberrations in the groups of follicular lymphoma and DLBCL revealed a pattern of clonal evolution from the changes rea(1)(p36), del(6q), +7, +12 or dup or trp(12)(q13q22), +der(18)t(14;18), and +21 in follicular lymphoma to the changes rea(1)(p36), del(6q), +6, +7, +9, rea(11)(q23), +12, -13 or del(13(q12q14), +18, +21, and +X in DLBCL. The clonal evolution of the secondary aberrations is thought to contribute to the progression of the disease. About 90% (16/18) of other types of NHL had abnormal karyotypes showing specific translocations or gene rearrangements consistent with the pathologic diagnosis. A comprehensive cytogenetics approach including SKY and interphase FISH using probes for specific genes, such as IGH, BCL2, CCND1, and ALK, is a very useful ancillary diagnostic tool for lymphomas. The combined approach also led to the identification of t(2;19)(p23;q13.1) as a new variant of t(2;5)(p23;q35) in a case of Ki-1-positive anaplastic large cell lymphoma with a null cell phenotype.     

Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature

Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.     

Interphase cytogenetics for 1p19q and t(1;19)(q10;p10) may distinguish prognostically relevant subgroups in extraventricular neurocytoma

Co-deletion of chromosome arms 1p and 19q, characteristic of oligodendroglial tumors, was recently found to be mediated by t(1;19)(q10;p10). To evaluate the prevalence of 1p19q co-deletion and t(1;19) in extraventricular neurocytomas (EVN), we studied tumors from 23 patients, including 13 females and 10 males (median age at diagnosis 34 years, range 2–76 years). Fluorescence in situ hybridization (FISH) studies were performed with probes targeting 1p36/1q25 and 19q13/19p13 to assess for 1p19q co-deletion, as well as chromosome 1 α-satellite and 19p12 to detect t(1;19)(q10;p10). FISH was successful in 21 (91%) cases and demonstrated 1p19q co-deletion in five cases (24%) or isolated 1p loss in two cases (10%). Evidence for t(1;19) was found in four (of five) cases with 1p19q co-deletion. Three tumors with 1p19q loss and t(1;19) demonstrated atypical histologic features, compared with one (of 17) tumors without 1p19q co-deletion ( P  = 0.01, Fisher exact test). In addition, tumors with t(1;19) showed increased mitotic activity compared with tumors without t(1;19) ( P  = 0.045; Wilcoxon rank sum test). The four patients with t(1;19) developed tumor recurrence (n = 3), or expired (n = 2) 3.5 to 5.5 years after first resection. These results suggest that 1p19q loss and t(1;19) occur in a subset of EVN, and may be associated with aggressive histology in these tumors.     

Nonrandom chromosomal abnormalities in acute lymphoblastic leukemia of childhood

The leukemic cell karyotype was studied in 103 children with acute lymphoblastic leukemia. An abnormal chromosome pattern was revealed in 81 of 98 patients studied before treatment (82.6%) and in the five children studied in relapse. Aside from specific chromosomal abnormalities defined by the Third International Workshop on Chromosomes in Leukemia, other nonrandom rearrangements were observed, particularly del(14)(q11-13), del(12)(p11-12), and t(1;19)(q22-23;p13), often associated with partial trisomy for 1q. Patients with del(14) had tumorous lymph-nodes or other extramedullary tumors. The course of the disease in these children was rapid. Patients with markers such as Ph, 6q-,14q+, and with a t(4;11) had a low incidence of complete remission and short survival. The most favorable course of the disease was observed in the group of children with over 50 chromosomes in the leukemic cells.